Hybrid Immunity Overcomes Defective Immune Response to COVID-19 Vaccination in Kidney Transplant Recipients.

Introduction: Comorbidities and immunosuppressive therapies are associated with reduced immune responses to primary COVID-19 mRNA vaccination in kidney transplant recipients (KTRs). In healthy individuals, prior SARS-COV-2 infection is associated with increased vaccine responses, a phenotype called hybrid immunity. In this study, we explored the potential influence of immune suppression on hybrid immunity in KTRs. Methods: Eighty-two KTRs, including 59 SARS-CoV-2-naïve (naïve KTRs [N-KTRs]) and 23 SARS-CoV-2-experienced (experienced KTRs [E-KTRs]) patients, were prospectively studied and compared to 106 healthy controls (HCs), including 40 SARS-CoV-2-naïve (N-HCs) and 66 SARS-CoV-2-experienced (E-HCs) subjects. Polyfunctional antibody and T cell responses were measured following 2 doses of BNT162b2 mRNA vaccine. Associations between vaccine responses and clinical characteristics were studied by univariate and multivariate analyses. Results: In naïve KTRs, vaccine responses were markedly lower than in HCs and were correlated with older age, more recent transplantation, kidney retransplantation after graft failure, arterial hypertension, and treatment with mycophenolate mofetil (MMF). In contrast, vaccine responses of E-KTRs were similar to those of HCs and were associated with time between transplantation and vaccination, but not with the other risk factors associated with low vaccine responses in naïve KTRs. Conclusion: In conclusion, hybrid immunity overcomes immune suppression and provides potent humoral and cellular immunity to SARS-CoV-2 in KTRs.

Sex- and species-associated differences in complement-mediated immunity in humans and rhesus macaques.

The complement system can be viewed as a "moderator" of innate immunity, "instructor" of humoral immunity, and "regulator" of adaptive immunity. While sex is known to affect humoral and cellular immune systems, its impact on complement in humans and rhesus macaques, a commonly used non-human primate model system, has not been well studied. To address this knowledge gap, we analyzed serum samples from 90 humans and 72 rhesus macaques for the abundance and activity of the complement system components. While sequences of cascade proteins were highly conserved, dramatically different levels were observed between species. Whereas the low levels detected in rhesus samples raised questions about the suitability of the test for use with macaque samples, differences in levels of complement proteins were observed in male and female humans. Levels of total and antibody-dependent deposition of C1q and C3b on a glycosylated antigen differed between humans and rhesus, suggesting differential recognition of glycans and balance between classical and alternative activation pathways. Functional differences in complement-mediated lysis of antibody-sensitized cells were observed in multiple assays and showed that human females frequently exhibited higher lytic activity than human males or rhesus macaques, which typically did not exhibit such sex-associated differences. Other differences between species and sexes were observed in more narrow contexts-for only certain antibodies, antigens, or assays. Collectively, these results expand knowledge of sex-associated differences in the complement system in humans, identifying differences absent from rhesus macaques.IMPORTANCEThe complement system is a critical part of host defense to many bacterial, fungal, and viral infections. In parallel, rich epidemiological, clinical, and biomedical research evidence demonstrates that sex is an important biological variable in immunity, and many sex-specific differences in immune system are intimately tied with disease outcomes. This study focuses on the intersection of these two factors to define the impact of sex on complement pathway components and activities. This work expands our knowledge of sex-associated differences in the complement system in humans and also identifies the differences that appear to be absent in rhesus macaques, a popular non-human primate model. Whereas differences between species suggest potential limitations in the ability of macaque model to recapitulate human biology, knowledge of sex-based differences in humans has the potential to inform clinical research and practice.

Effector functions are required for broad and potent protection of neonatal mice with antibodies targeting HSV glycoprotein D.

Multiple failed herpes simplex virus (HSV) vaccine candidates induce robust neutralizing antibody (Ab) responses in clinical trials, raising the hypothesis that Fc-domain-dependent effector functions may be critical for protection. While neonatal HSV (nHSV) infection results in mortality and lifelong neurological morbidity in humans, it is uncommon among neonates with a seropositive birthing parent, supporting the hypothesis that Ab-based therapeutics could protect neonates from HSV. We therefore investigated the mechanisms of monoclonal Ab (mAb)-mediated protection in a mouse model of nHSV infection. For a panel of glycoprotein D (gD)-specific mAbs, neutralization and effector functions contributed to nHSV-1 protection. In contrast, effector functions alone were sufficient to protect against nHSV-2, exposing a functional dichotomy between virus types consistent with vaccine trial results. Effector functions are therefore crucial for protection by these gD-specific mAbs, informing effective Ab and vaccine design and demonstrating the potential of polyfunctional Abs as therapeutics for nHSV infections.

Sex and species associated differences in Complement-mediated immunity in Humans and Rhesus macaques.

The complement system can be viewed as a 'moderator' of innate immunity, 'instructor' of humoral immunity, and 'regulator' of adaptive immunity. While sex and aging are known to affect humoral and cellular immune systems, their impact on the complement pathway in humans and rhesus macaques, a commonly used non-human primate model system, have not been well-studied. To address this knowledge gap, we analyzed serum samples from 90 humans and 75 rhesus macaques for the abundance and activity of the complement system components. While sequences of cascade proteins were highly conserved, dramatically different levels were observed between species. Whereas the low levels detected in rhesus samples raised questions about the suitability of the test, differences in levels of complement proteins were observed in male and female humans. Levels of total and antibody-dependent deposition of C1q and C3b on a glycosylated antigen differed between human and rhesus, suggesting differential recognition of glycans. Functional differences in complement-mediated lysis of antibody-sensitized cells were observed in multiple assays and showed that human females frequently exhibited higher lytic activity than human males or rhesus macaques, which typically did not exhibit such sexual dimorphism. Other differences between species and sexes were observed in more narrow contexts-for only certain antibodies, antigens, or assays. Collectively, these results expand our knowledge of sexual dimorphism in the complement system in humans, identifying differences that appear to be absent from rhesus macaques.

Antibody effector functions are required for broad and potent protection of neonates from herpes simplex virus infection.

The failure of multiple herpes simplex virus (HSV) vaccine candidates that induce neutralizing antibody responses raises the hypothesis that other activities, such as Fc domain-dependent effector functions, may be critical for protection. While neonatal HSV (nHSV) infection result in mortality and lifelong neurological morbidity in humans, it is uncommon among neonates with a seropositive birthing parent, suggesting the potential efficacy of antibody-based therapeutics to protect neonates. We therefore investigated the mechanisms of monoclonal antibody (mAb)-mediated protection in a mouse model of nHSV infection. Both neutralization and effector functions contributed to robust protection against nHSV-1. In contrast, effector functions alone were sufficient to protect against nHSV-2, exposing a functional dichotomy between virus types that is consistent with vaccine trial results. Together, these results emphasize that effector functions are crucial for optimal mAb-mediated protection, informing effective Ab and vaccine design, and demonstrating the potential of polyfunctional Abs as potent therapeutics for nHSV infections.

Foundations for improved vaccine correlate of risk analysis using positive-unlabeled learning.

Insights into mechanisms of protection afforded by vaccine efficacy field trials can be complicated by both low rates of exposure and protection. However, these barriers do not preclude the discovery of correlates of reduced risk (CoR) of infection, which are a critical first step in defining correlates of protection (CoP). Given the significant investment in large-scale human vaccine efficacy trials and immunogenicity data collected to support CoR discovery, novel approaches for analyzing efficacy trials to optimally support discovery of CoP are critically needed. By simulating immunological data and evaluating several machine learning approaches, this study lays the groundwork for deploying Positive/Unlabeled (P/U) learning methods, which are designed to differentiate between two groups in cases where only one group has a definitive label and the other remains ambiguous. This description applies to case-control analysis designs for field trials of vaccine efficacy: infected subjects, or cases, are by definition unprotected, whereas uninfected subjects, or controls, may have been either protected or unprotected but simply never exposed. Here, we investigate the value of applying P/U learning to classify study subjects using model immunogenicity data based on predicted protection status in order to support new insights into mechanisms of vaccine-mediated protection from infection. We demonstrate that P/U learning methods can reliably infer protection status, supporting the discovery of simulated CoP that are not observed in conventional comparisons of infection status cases and controls, and we propose next steps necessary for the practical deployment of this novel approach to correlate discovery.